Despite advancements in the prevention and treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death, disability, and health costs in the US and worldwide. During atherosclerosis, there is increased inflammation and the development of endothelial dysfunction. Concurrent with these processes, the endothelial glycocalyx, a layer of glycoproteins and polysaccharides that interfaces with blood flow, is degraded. The glycocalyx is a major structure maintaining vascular barrier function, reducing thrombosis during vascular injury and serves as an anti-inflammatory factor that reduces the extravasation of circulating immune cells. In this proposal, we aim to create glycocalyx-mimetic therapeutics that circulate in the blood and accumulate on the surface of the endothelial cells to restore barrier function during atherosclerosis and vascular injury. To this end, we will explore the use of marine polysaccharides that have a structure similar to molecules in the glycocalyx and can be given as oral therapy for atherosclerosis. Our preliminary and published studies have shown that the marine polysaccharide rhamnan sulfate can accumulate on the surface of endothelial cells and reduces inflammation and lipid uptake in endothelial cells. In addition, we found that rhamnan sulfate prevented arteriothrombosis during vascular injury. We will evaluate rhamnan sulfate as a potential therapy for reducing the formation of atherosclerotic plaques and reducing vascular inflammation. To achieve this goal, we will carry out the following specific aims: (1) examine the effectiveness of marine polysaccharides in reducing inflammation and lipid uptake in vascular cells; and (2) examine the utility of rhamnan sulfate in reducing atherosclerosis following vascular injury in mice. Together these studies will provide an evaluation of the therapeutic potential of rhamnan sulfate for vascular disease and injury. As rhamnan sulfate is relatively inexpensive and has been consumed by millions of people as part of their diet, it would present an easily implementable adjuvant therapy to lipid lowering drugs and other treatments for atherosclerotic disease.